Aqueous drug composition having property of reversible thermosetting gelation

ABSTRACT

An aqueous drug composition having property of reversible thermosetting gelation for ophthalmic, dermatological and body cavitical use which comprises effective amount of drugs used for pharmaceutical therapy or diagnosis, methylcellulose, citric acid and polyethylene glycol and has a pH of 3 to 10, characterized in that said aqueous drug composition is fluid liquid before administration or application and forms gel at a body temperature of a local region immediately after administration or application.

TECHNICAL FIELD

The present invention relates to an aqueous drug composition havingproperty of reversible thermosetting gelation which comprises apharmacologically effective component, methylcellulose, citric acid andpolyethylene glycol (PEG). More specifically, it relates to an aqueousdrug composition characterized in that said aqueous drug compositions isfluid liquid at room temperature or lower and, when administered to eyesor body cavities or spread on skin, gelation happens at body temperatureof mammal, so as to achieve a greater degree of bioavailability of thepharmacologically effective component and maintain the effect of thedrugs for long period.

BACKGROUND ART

Hitherto, many aqueous drug compositions which are liquid at roomtemperature or lower and form a semi-solid or gel at body temperature ofmammal have been disclosed for aqueous drug compositions whicheffectively release a pharmacologically effective component to mammal tobe treated. U.S. Pat. No. 4,188,373 discloses aqueous drug compositionshaving property of thermosetting gelation, which comprise PLURONIC(trademark) and form gel by heating, and a desired sol-gel transitiontemperature thereof is obtained by controlling the concentration ofPLURONIC. Moreover, U.S. Pat. Nos. 4,474,751, 4,474,752, 4,474,753 and4,478,822 disclose drug delivery systems utilizing aqueous drugcompositions having property of thermosetting gelation. The uniquefeatures of these systems are that both the sol-gel transitiontemperature and/or the rigidity of the gel can be modified by adjustmentof the pH and/or the ionic strength and the polymer concentration. Morerecently, aqueous drug compositions, which form gel at a local region bychanging pH and increasing temperature simultaneously (PCT WO 91/19481),are proposed.

However, the safety of the gelling materials used in these aqueouscompositions is not necessarily certified with respect to all of theregions to be treated, and the high viscosity of the compositions inliquid state due to the high concentration of polymer in aqueouscompositions results in the disadvantage that it cannot be easily usedin a certain regions to be treated (for example, eyes). Japanese PatentApplication Laid-open 62-181228 discloses a aqueous drug compositionhaving property of sol-gel phase transition by ionic strength. Thiscomposition is characterized in that the concentration of the materialsgiving rise to a sol-gel phase transition is 10-100 times less than thatof the aforesaid aqueous drug compositions having property ofthermosetting gelation, and that it has no danger of gelation even ifthe surrounding temperature rises during storage, but it can be appliedto only the specific region (for example, eyes).

On the other hand, it is well known that an aqueous solution ofmethylcellulose forms gel by heating and reverses to sol by cooling, inother words, its sol-gel phase transition is reversible, and researcheson its mechanism have been considerably made.

OOba reports the relation of the degree of polymerization ofmethylcellulose and the concentration of methylcellulose to the gellingtemperature, and the modification of gelling temperature by addition ofion, based on the experiment where an aqueous solution ofmethylcellulose is heated at a fixed rate to form gel (Hakodatetechnical specialized high school bulletin, No.22, 113-120, 1987).However, there is no description about aqueous compositions comprisingmethylcellulose which form gel at around body temperature of mammal.

Moreover, E. Heymann has determined the sol-gel transition temperatureof an aqueous solution of methylcellulose with the content of methoxylgroup of 35.4% (concentration of methylcellulose: 1.6%) when it iscombined with salts. However, according to the experiment of the presentinventors, when using methylcellulose (content of methoxyl group:26-33%) as used in the present invention, the aqueous solution ofmethylcellulose with 0.2 mol of salt concentration (concentration ofmethylcellulose: 1.6%) has never formed gel at around body temperatureof mammal.

DISCLOSURE OF INVENTION

After the present inventors have diligently conducted many researches inorder to develop aqueous drug compositions which are liquid at roomtemperature or lower and form gel at body temperature of mammal by usinggelling materials which can be administered to any regions to be treatedand whose safeties have been certified, they have found that theexcellent aqueous drug compositions which form gel at the temperature ofa local region and give no discomfort after administration can beobtained by mixing the appropriate amounts of methylcelullose, citricacid and PEG having a particular range of molecular weight, andcompleted the present invention.

That is, the present invention relates to an aqueous drug compositionhaving property of reversible thermosetting gelation comprisingeffective amount of drugs used for pharmaceutical therapy or diagnosis,characterized in that the said composition comprises 0.2 to 2.1 (W/V) %of methylcellulose (the content of methoxyl group is within the range of26 to 33%), 1.2 to 2.3 (W/V) % of citric acid, 0.5 to 13 (W/V) % ofpolyethylene glycol and a pharmaceutically acceptable pH adjusting agentin an amount sufficient to adjust pH of composition within the range of3 to 10. The aqueous drug composition according to the present inventioncan be easily administered or spread on the region to be treated in afixed amount since it has good fluidity at room temperature or lower,and moreover, since it forms gel immediately after administration, itcan keep a good residence of drugs in any regions and maintain aprolonged effect of drugs.

One of the excellent advantageous features of the composition accordingto the present invention is that it is liquid with low viscosity attemperature less than body temperature of mammal because of the lowconcentration of methylcellulose polymer and that it forms semi-solid orgel with very high viscosity immediately after contacted with mammal tobe treated. Further, another advantageous feature is that thecomposition promptly arrives at the region to be treated and shows goodcontact with the region since it is liquid with low viscosity. Moreover,another advantageous feature is that even if administered to the skin orbody cavities of mammal, the pain to be given to the patient can beminimized because it shows no stimulus on eyes.

Any methylcelluloses can be used alone or as a mixture thereof as themethylcellulose (content of methoxyl group: 26-33%) used in the presentinvention, so long as it has a viscosity of 2% aqueous solution withinthe range of 13-12,000 millipascal.sec at 20° C. The content of methoxylgroup is preferably within the range of from 26 to 33% in view of thesolubility to water. Such methylcelluloses are sold by Shinetsu ChemicalIndustry Inc. as METOLOSE™ SM 15, SM 25, SM 100, SM 400, SM1500, SM4000,SM 8000 (the number represents the viscosity of 2% aqueous solution at20° C., millipascal.sec), and by Matsumoto Oil and Fat PharmaceuticalIndustry Inc. as MARPOLOSE™ M, and from Dow chemical Co. as METOCEL™A,and all commodities can be easily obtained.

The PEG's used in the present invention are sold by Wako JunyakuIndustry Inc. as PEG-200, PEG-300, PEG-600, PEG-1000, PEG-1540,PEG-2,000, PEG-4,000, PEG-6,000, PEG-20,000, PEG-50,000, PEG-500,000,PEG-2,000,000 and PEG-4,000,000, and from Japan Oil and Fat Inc. asMACROGOL-200, MACROGOL-300, MACROGOL-400, MACROGOL-600, MACROGOL-1,500,MACROGOL-1,540, MACROGOL-4,000, MACROGOL-6,000 and MACROGOL-20,000.

The weight-average molecular weight of the PEG used in the presentinvention is preferably 300 to 50,000, and particularly 1,000 to 20,000.When the weight-average molecular weight is less than 300, thecomposition tends to be hard to form gel at a local region, and when itis more than 50,000, the viscosity in liquid state increases and it isnot preferred. Two or more kinds of PEG can be mixed to adjust theweight-average molecular weight thereof within the above optimum range.

In the embodiment of the aqueous drug composition having property ofreversible thermosetting gelation according to the present invention,the range of the concentration of methylcellulose, citric acid and PEGmust be limited for the following reasons.

The concentration of the methylcellulose used in the present inventionis within the range of 0.2 to 2.1 (W/v) %. When the concentration ofmethylcellulose is less than 0.2 (W/V) %, the composition becomes hardto form gel at a local region and, when the concentration is more than2.1 (W/V) %, the sol shows unduly high viscosity which results inincorrect dosage and it is not preferred.

The concentration of the citric acid is within the range of 1.2 to 2.3(W/V) %. When the concentration of citric acid is less than 1.2 (w/v) %,the composition becomes hard to form gel at a local region and, when theconcentration is more than 2.3 (w/V) %, it is not preferred in view ofthe stimulus on eyes.

The concentration of the PEG is within the range of 0.5-13 (W/V) %. Whenthe concentration of PEG is less than 0.5 (W/V) %, the compositionbecomes hard to form gel at a local region and hence loses practicalvalue and, when the concentration is more than 13 (W/V) %, the sol showshigh viscosity and it is not preferred.

Furthermore, the gelling temperature of the composition is preferablyfrom about 20° C. to about 40° C. since it is desired that thecomposition is liquid at room temperature or lower and forms gel at bodytemperature of mammal.

The aqueous drug composition of the present invention may be used forthe therapy and diagnosis of diseases of, for example, eyes, skin andbody cavities. The examples of medicines and diagnostics which can becomprised in the composition of the present invention and administeredto eyes of mammal, are as follows: chemotherapeutics such asamphotericin B, norfloxacin, miconazole nitrate, ofloxacin andidoxuridine; antibiotics preparation such as chloramphenicol, colistinsodium methanesulfonate, carbenicillin sodium and gentamicin sulfate;antiallergic agents such as 3'-(1H-tetrazol-5-yl)oxanilic acid(MTCC),ketotifen fumarate and sodium cromoglicate; anti-inflammatory agentssuch as betamethasone sodium phosphate, dexamethasone, fluorometholone,glycyrrhizinate dipotassium, lysozyme chloride, diclofenac sodium,pranoprofen, indomethacin, cortisone acetate, azulene, allantoin andε-aminocaproic acid; miotics and preparations such as pilocarpinehydrochloride and carbachol; vitamin preparations such as flavin adeninedinucleotide, pyridoxal phosphate and cyanocobalamin; vasoconstrictorssuch as naphazoline nitrate and phenylephrine hydrochloride;antihistamines such as chlorpheniramine maleate and diphenhydraminehydrochloride; mydriatics and preparations such as tropicamide;antiglaucoma drugs such as timolol maleate and carteolol hydrochloride;anticataract drugs such as glutathione and pirenoxine; local anestheticssuch as lidocaine hydrochloride and oxybuprocaine hydrochloride;ophthalmic diagnostic agents such as fluorescein sodium;immunosuppressive agents such as ciclosporin and azathioprine;antimetabolic agents such as fluorouracil and tegafur; decongestantssuch as epinephrine hydrochloride; anti diabetic retinopathy agent suchas [5-(3-thienyl)tetrazol-1-yl]acetic acid(TAT); amino acids such aschondroitin sulfate sodium and aminoethylsulfonic acid; autonomic nerveagents such as neostigmine methylsulfate, and mixtures thereof, andother drugs may be used for the theraphy of the symptom and focus ofeyes.

The examples of drugs which can be comprised in the composition of thepresent invention and administered to skin of mammal, are as follows:anti-dermoinfectives such as bifonazole, siccanin, bisdequaliniumacetate, clotrimazole and salicylic acid; dermatics for purulence suchas sulfamethoxazole sodium, erythromycin and gentamicin sulfate;analgesics and anti-inflammatory agents such as indomethacin,ketoprofen, betamethasone valerate and fluocinolone acetonide;anti-itchings such as diphenhydramine; local anesthetics such asprocaine hydrochloride and lidocaine hydrochloride; antimicrobials fordermatologic use such as iodine, povidone iodine, benzalkonium chlorideand chlorhexidine gluconate.

The examples of drugs which can be comprised in the composition of thepresent invention and administered to body cavities of mammal, that is,rectum, urethra, nasal cavity, vagina, auditory meatus, oral cavity andbuccal pouch, are as follows: antihistamines such as diphenhydraminehydrochloride and chlorpheniramine maleate; agents affecting genitalorgans such as clotrimazole, naphazoline nitrate, ketotifen fumarate andmiconazole nitrate; agents for otic and nosal use such as tetryzolinehydrochloride; bronchodilators such as aminophylline; antimetabolicagents such as fluorouracil; hypnotics and sedatives such as diazepam;antipyretics,analgesics and anti-inflammatory agents such as aspirin,indomethacin, sulindac, phenylbutazone and ibuprofen; adrenal hormonepreparations such as dexamethasone, triamcinolone and hydrocortisone;local anesthetics such as lidocaine hydrochloride; dermatics forpurulence such as sulfisoxazole, kanamycin, tobramycin and erythromycin;synthetic antibacterials such as norfloxacin and nalidixic acid.

Generally, the composition preferably contains from about 0.001% toabout 10% by weight of the effective drug, though it may vary dependingon the type of the drug.

The examples of the pH adjusting agents used in the composition of thepresent invention include acids such as hydrochloric acid, sulfuricacid, boric acid, phosphoric acid and acetic acid and bases such assodium hydroxide, monoethanolamine, diethanolamine and triethanolamine.

If necessary, the aqueous drug composition of the present invention maycontain pharmaceutically acceptable buffering agents, salts,preservatives and solubilizing agents and the like. The examples of thepreservatives may include invert soaps such as benzalkonium chloride,benzethonium chloride and chlorhexyzine gluconate, parabens such asmethylparaben, ethylparaben, propylparaben and butylparaben, alcoholssuch as chlorobutanol, phenylethylalcohol and benzyl alcohol, organicacids and salts thereof such as dehydro sodium acetate, sorbic acid andsodium sorbate. Moreover, surfactants or chelating agents may besuitably added to the composition. Generally, these components may beused within the range of about 0.001 to 2% by weight, and preferablywithin the range of about 0.002 to 1% by weight. The examples ofbuffering agents include alkaline metal salts of acids such asphosphoric acid, boric acid, acetic acid, tartaric acid, lactic acid andcarbonic acid, amino acids such as glutamic acid, ε-aminocaproic acid,aspartic acid, glycine, arginine and lysine, and taurine,tris(hydoroxymethyl) aminomethane. These buffering agents may be addedto the composition in a sufficient amount to maintain pH within therange of 3 to 10.

The examples of the solubilizing agents include POLYSORBATE80,polyoxyethylene hydrogenated castor oil and cyclodextrin and they may beused within a range of 0 to 15% by weight.

The process of preparing the aqueous drug composition of the presentinvention is not particularly restricted and, for example, comprisesdissolving citrate and PEG in sterilized water, adjusting the pH of thissolution with a pH adjusting agent, adding drugs and necessarypreservatives, adding a solution where methylcellulose is dissolved insterilized water, adjusting pH again, filling up the volume of themixture with sterilized water and stirring the composition with cooling.If necessary, after this procedure, a variety of additive, for example,buffering agents, salts and preservatives, may be added. Moreover, ifdrugs are slightly soluble or insoluble, they may be suspended orsolubilized by solubilizing agents before use.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 shows the relation of METOLOSE concentration and pH in theaqueous composition to gelling temperature. The axis of ordinaterepresents the concentration of METOLOSE SM 400 ((W/V)%) and the axis ofabscissa represents pH.

FIG. 2 shows the time course of timolol concentration in the plasma ofthe albino rabbit following the topical instillation of the aqueouscomposition. The axis of ordinate represents the concentration oftimolol (ng/ml) and the axis of abscissa represents time (hour).

BEST MODE FOR CARRYING OUT THE INVENTION

The following examples are provided to illustrate a variety ofembodiment of the present invention and are not intended to limit therange of the present invention.

EXAMPLES Example 1

2.3 g of citric acid, 6.0 g of POLYETHYLENE GRYCOL 4000 (weight-averagemolecular weight is 3000, available from Wako Junyaku Industry Inc.),0.5 g of chlorobutanol are dissolved in 50 ml of sterilized water. Tothis added are 0.1 g of idoxuridine dissolved in 10 ml of 3N sodiumhydroxide and 0.5 g of METOLOSE SM 400 (available from Shinetsu ChemicalIndustry Inc.) dissolved in 25 ml of sterilized water. Then, pH isadjusted to 6.0 with 3N sodium hydroxide and the volume of the mixtureis filled up to 100 ml with sterilized water, and the components aredissolved by stirring well with ice cooling to give eye drops.

Example 2

2.3 g of citric acid, 6.0 g of POLYETHYLENE GRYCOL 4000 are dissolved in50 ml of sterilized water and pH is adjusted to 5.0 with 3N sodiumhydroxide. To this added are 0.3 g of norfloxacin, 0.005 g ofbenzalkonium chloride and, furthermore, 0.5 g of METOLOSE SM 400dissolved in 25 ml of sterilized water. Then, pH is adjusted to 5.5 with3N sodium hydroxide and the volume of the mixture is filled up to 100 mlwith sterilized water, and the components are dissolved by stirring wellwith ice cooling to give eye drops.

Examples 3-6

By a method similar to that of Example 2, eye drops of whichcompositions are shown in Table 1, are prepared.

Example 7

0.026 g of methylparaben and 0.014 g of propylparaben are added to 50 mlof sterilized water prewarmed to about 60° C. and are well stirred to bedissolved. After this solution is cooled to room temperature, 2.3 g ofcitric acid, 6.0 g of POLYETHYLENE GRYCOL 4000 and 0.25 g ofchlorobutanol are added to this and dissolved, then pH is adjusted to5.0 with monoethanolamine. To this mixture, 0.1 g of MTCC is added and,furthermore, 0.5 g of METOLOSE SM 400 dissolved in 25 ml of sterilizedwater is added. Then pH is adjusted to 5.5 with monoethanolamine and thevolume of the mixture is filled up to 100 ml by sterilized water and thecomponents are dissolved by stirring well with ice cooling to give eyedrops.

Example 8

By a method similar to that of Example 7, eye drops of whichcompositions are shown in Table 1, are prepared.

Example 9

0.1 g of pranoprofen, 2.3 g of citric acid and 6.0 g of POLYETHYLENEGRYCOL 4000 are added to 50 ml of sterilized water and stirred well,then pH is adjusted to 6.5 with monoethanolamine. To this added is 0.005g of benzalkonium chloride and, furthermore, 0.5 g of METOLOSE SM 400dissolved in 25 ml of sterilized water. Then pH is adjusted to 7.4 withmonoethanolamine and the volume of the mixture is filled up to 100 ml bysterilized water, and the components are dissolved by stirring well withice cooling to give eye drops.

Example 10

0.026 g of methylparaben and 0.014 g of propylparaben are added to 50 mlof sterilized water prewarmed to about 60° C. and are stirred well to bedissolved. After this solution is cooled to room temperature, 0.05 g ofnaphazoline nitrate, 3.5 g of sodium citrate dihydrate and 6.0 g ofPOLYETHYLENE GRYCOL 4000 are added to the solution and dissolved. Tothis mixture, 0.5 g of METOLOSE SM 400 dissolved in 25 ml of sterilizedwater is added and stirred well. Then pH is adjusted to 5.8 with 1Nhydrochloric acid and the volume of the mixture is filled up to 100 mlby sterilized water, and the components are dissolved by stirring wellwith ice cooling to give eye drops.

Examples 11-13

By a method similar to that of Example 10, eye drops of whichcompositions are shown in Table 1, are prepared.

Example 14

0.34 g of timolol maleate, 3.5 g of sodium citrate dihydrate, 6.0 g ofPOLYETHYLENE GRYCOL 4000 and 0.005 g of benzalkonium chloride are addedto 50 ml of sterilized water and dissolved. To this, 0.5 g of METOLOSESM 400 dissolved in 25 ml of sterilized water is added and stirred well.Then, pH is adjusted to 6.8 with 1N hydrochloric acid or 1N sodiumhydroxide and the volume of the mixture is filled up to 100 ml withsterilized water and the components are dissolved by stirring well withice cooling to give eye drops.

Examples 15-19

By a method similar to that of Example 14, eye drops of whichcompositions are shown in Table 1, are prepared.

Examples 20-22

By a method similar to that of Example 14, agents for dermal use ofwhich compositions are shown in Table 1, are prepared.

Example 23

By a method similar to that of Example 10, agents for dermal use ofwhich compositions are shown in Table 1, are prepared.

Example 24-31

By a method similar to that of Example 14, agents for body cavitical useof which compositions are shown in Table 1, are prepared.

                  TABLE 1                                                         ______________________________________                                        Ex-                                 Gelling                                   ample Component           W/V %     temp.                                     ______________________________________                                         1    Idoxuridine          0.1      36                                              SM 400               0.5                                                      Citric acid          2.3                                                      PEG 4000             6.0                                                      Chlorobutanol        0.5                                                      3N NaOH             to pH 6.0                                            2    Norfloxacin          0.3      36                                              SM 400               0.5                                                      Citric acid          2.3                                                      PEG 4000             6.0                                                      Benzalkonium chloride                                                                              0.005                                                    3N NaOH             to pH 5.5                                            3    Gentamicin sulfate   0.3 g titer                                                                            36                                              SM 400               0.5                                                      Citric acid          2.3                                                      PEG 4000             6.0                                                      Benzalkonium chloride                                                                              0.005                                                    3N NaOH             to pH 7.0                                            4    Sodium cromoglicate  2.0      36                                              SM 400               0.5                                                      Citric acid          2.3                                                      PEG 4000             6.0                                                      Benzalkonium chloride                                                                              0.01                                                     3N NaOH             to pH 6.5                                            5    Betamethasone sodium phosphate                                                                     0.1      34                                              SM 400               0.5                                                      Citric acid          2.3                                                      PEG 4000             6.0                                                      Benzalkonium chloride                                                                              0.01                                                     POLYSORBATE 80       0.2                                                      3N KOH              to pH 8.2                                            6    Lidocaine hydrochloride                                                                            0.5      36                                              SM 400               0.5                                                      Citric acid          2.3                                                      PEG 4000             6.0                                                      Benzalkonium chloride                                                                              0.005                                                    Triethanolamine     to pH 6.5                                            7    MTCC                 0.1      36                                              SM 400               0.5                                                      Citric acid          2.3                                                      PEG 4000             6.0                                                      Methylparaben        0.026                                                    Propylparaben        0.014                                                    Chlorobutanol        0.25                                                     Monoethanolamine    to pH 5.5                                            8    Flavin adenine dinucleotide                                                                        0.05     36                                              SM 400               0.5                                                      Citric acid          2.3                                                      PEG 4000             6.0                                                      Methylparaben        0.026                                                    Propylparaben        0.014                                                    Diethanolamine      to pH 6.7                                            9    Pranoprofen          0.1      34                                              SM 400               0.5                                                      Citric acid          2.3                                                      PEG 4000             6.0                                                      Benzalkonium chloride                                                                              0.005                                                    Monoethanolamine    to pH 7.4                                           10    Naphazoline nitrate  0.05     36                                              SM 400               0.5                                                      Sodium citrate dihydrate                                                                           3.5                                                      PEG 4000             6.0                                                      Methylparaben        0.026                                                    Propylparaben        0.014                                                    1N HCl              to pH 5.8                                           11    Pilocarpine hydrochloride                                                                          0.5      36                                              SM 400               0.5                                                      Sodium citrate dihydrate                                                                           3.5                                                      PEG 4000             6.0                                                      Methylparaben        0.026                                                    Propylparaben        0.014                                                    Chlorobutanol        0.25                                                     1N HCl              to pH 5.2                                           12    Pirenoxine           0.005    36                                              SM 400               0.5                                                      Sodium citrate dihydrate                                                                           3.5                                                      PEG 4000             9.0                                                      Methylparaben        0.026                                                    Propylparaben        0.014                                                    1N HCl              to pH 6.0                                           13    TAT                  2.2      36                                              SM 400               0.5                                                      Sodium citrate dihydrate                                                                           3.5                                                      PEG 4000             6.0                                                      Methylparaben        0.026                                                    Propylparaben        0.014                                                    POLYSORBATE 80       0.005                                                    1N NaOH             to pH 5.5                                           14    Timolol maleate      0.34     36                                              SM 400               0.5                                                      Sodium citrate dihydrate                                                                           3.5                                                      PEG 4000             6.0                                                      Benzalkonium chloride                                                                              0.005                                                    1N HCl or 1N NaOH   to pH 6.8                                           15    Timolol maleate      0.34     32                                              SM 400               0.7                                                      SM 15                0.7                                                      Sodium citrate dihydrate                                                                           3.5                                                      PEG 4000             2.0                                                      Benzalkonium chloride                                                                              0.005                                                    1N HCl or 1N NaOH   to pH 6.8                                           16    Ciclosporin          0.05     36                                              SM 400               0.5                                                      Sodium citrate dihydrate                                                                           3.5                                                      PEG 4000             6.0                                                      Benzalkonium chloride                                                                              0.005                                                    1N HCl              to pH 6.0                                           17    Fluorouracil         1.0      34                                              SM 400               0.5                                                      Sodium citrate dihydrate                                                                           3.5                                                      PEG 4000             6.0                                                      Benzalkonium chloride                                                                              0.005                                                    1N NaOH             to pH 8.4                                           18    Fluorescein sodium   1.0      34                                              SM 15                2.1                                                      Sodium citrate dihydrate                                                                           3.5                                                      PEG 20000            1.0                                                      1N HCl or 1N NaOH   to pH 7.4                                           19    Tropicamide          0.5      36                                              Phenylephrine hydrochloride                                                                        0.5                                                      SM 400               0.5                                                      Sodium citrate dihydrate                                                                           3.5                                                      PEG 4000             6.0                                                      Benzalkonium chloride                                                                              0.005                                                    1N HCl              to pH 5.5                                           20    Clotrimazole         1.0      26                                              SM 1500              2.1                                                      Sodium citrate dihydrate                                                                           1.8                                                      PEG 4000             5.0                                                      Benzalkonium chloride                                                                              0.01                                                     1N HCl or 1N NaOH   to pH 7.0                                           21    Diphenhydramine hydrochloride                                                                      1.0      28                                              SM 1500              2.1                                                      Sodium citrate dihydrate                                                                           1.8                                                      PEG 4000             5.0                                                      Benzalkonium chloride                                                                              0.01                                                     1N HCl              to pH 5.5                                           22    Povidone iodine      5.0      32                                              SM 1500              2.1                                                      Sodium citratedihydrate                                                                            1.8                                                      PEG 4000             5.0                                                      1N HCl              to pH 3.0                                           23    Indomethacin         1.0      26                                              SM 1500              2.1                                                      Sodium citrate dihydrate                                                                           1.8                                                      PEG 4000             5.0                                                      Methylparaben        0.1                                                      1N HCl or 1N NaOH   to pH 7.0                                           24    Miconazole nitrate   1.0      28                                              SM 1500              2.1                                                      Sodium citrate dihydrate                                                                           1.8                                                      PEG 4000             5.0                                                      1N HCl              to pH 5.5                                           25    Tetryzoline hydrochloride                                                                          0.1      26                                              SM 1500              2.1                                                      Sodium citrate dihydrate                                                                           1.8                                                      PEG 4000             5.0                                                      Benzalkonium chloride                                                                              0.005                                                    1N HCl              to pH 6.5                                           26    Tetryzoline hydrochloride                                                                          0.1      36                                              SM 8000              1.0                                                      Sodium citrate dihydrate                                                                           1.8                                                      PEG 4000             5.0                                                      Benzalkonium chloride                                                                              0.005                                                    1N HCl              to pH 6.5                                           27    Tetryzoline hydrochloride                                                                          0.1      22                                              SM 1500              2.1                                                      Sodium citrate dihydrate                                                                           1.8                                                      PEG 4000            13.0                                                      Benzalkonium chloride                                                                              0.005                                                    1N HCl              to pH 6.5                                           28    Aminophylline        2.5      26                                              SM 1500              2.1                                                      Sodium citrate dihydrate                                                                           1.8                                                      PEG 4000             5.0                                                      Benzalkonium chloride                                                                              0.005                                                    1N NaOH             to pH 9.0                                           29    Diazepam             0.5      26                                              SM 1500              2.1                                                      Sodium citrate dihydrate                                                                           1.8                                                      PEG 4000             5.0                                                      Benzalkonium chloride                                                                              0.005                                                    1N HCl              to pH 6.5                                           30    Dexamethasone        0.1      26                                              SM 1500              2.1                                                      Sodium citrate dihydrate                                                                           1.8                                                      PEG 4000             5.0                                                      Benzalkonium chloride                                                                              0.005                                                    1N HCl              to pH 5.5                                           31    Erythromycin         0.1      28                                              SM 1500              2.1                                                      Sodium citrate dihydrate                                                                           1.8                                                      PEG 4000             5.0                                                      Benzalkonium chloride                                                                              0.005                                                    1N HCl or 1N NaOH   to pH 7.0                                           ______________________________________                                    

Test Example 1 (Concentration of METOLOSE, pH and gelling temperature)

3.5 g of sodium citrate dihydrate and 6.0 g of POLYETHYLENE GRYCOL 4000were dissolved in 50 ml of sterilized water, then, 0.3 to 2. 0 g ofMETOLOSE SM 400 dissolved in 25 ml of sterilized water was added to thesolution and pH was adjusted to 3.0 to 10.0 with 3N HCl or 3N NaOH, thevolume of the mixture was filled up to 100 ml by sterilized water andthe components were dissolved by stirring well with ice cooling toprepare an aqueous composition. The gelling temperature was determinedfor each aqueous composition. The results obtained are shown in FIG. 1.

Test Example 2 (Test of feeling when applied to human)

1.9 to 2.9 g of citric acid and 4.2 g of POLYETHYLENE GRYCOL 4000 weredissolved in 50 ml of sterilized water, then pH was adjusted to 6.8 with3N NaOH, the volume of the mixture was filled up to 100 ml withsterilized water and the components were dissolved by stirring well withice cooling to prepare the aqueous compositions 1 to 4. Further, 1.9 to2.9 g of citric acid and 4.2 g of POLYETHYLENE GRYCOL 4000 are dissolvedin 50 ml of sterilized water, pH is adjusted to 6.0 with diethanolamine.To this added was 0.7 g of METOLOSE SM 400 dissolved in 25 ml ofsterilized water and then, pH was adjusted to 6.8 with diethanolamineand the volume of the mixture was filled up to 100 ml with sterilizedwater and the components were dissolved by stirring well with icecooling to prepare the aqueous compositions 5 to 8.

As to the stimulus on eyes, the sensory test was carried out in thepanel of twenty persons. The standard of evaluation are as follows: "-"represents "non-stimulus", "+" represents "slight smart" and "++"represents "smart". The results of this test are shown in Tables 2 and3.

                  TABLE 2                                                         ______________________________________                                                  Methyl-                                                                       cellulose                                                                     SM-400    PEG 4000  Citric acid                                     Aqueous   conc.     conc.     conc..sup.1)                                                                          Stimulus                                composition                                                                             (W/V) %   (W/V) %   (W/V) % on eyes                                 ______________________________________                                        Composition 1                                                                           0.7       4.2       1.9     -                                       Composition 2                                                                           0.7       4.2       2.3     -                                       Composition 3                                                                           0.7       4.2       2.5     +                                       Composition 4                                                                           0.7       4.2       2.9     ++                                      ______________________________________                                         .sup.1) Sodium hydroxide was used as a pH adjusting agent.               

                  TABLE 3                                                         ______________________________________                                                  Methyl-                                                                       cellulose                                                                     SM-400    PEG 4000  Citric acid                                     Aqueous   conc.     conc.     conc..sup.1)                                                                          Stimulus                                composition                                                                             (W/V) %   (W/V) %   (W/V) % on eyes                                 ______________________________________                                        Composition 5                                                                           0.7       4.2       1.9     -                                       Composition 6                                                                           0.7       4.2       2.3     -                                       Composition 7                                                                           0.7       4.2       2.5     +                                       Composition 8                                                                           0.7       4.2       2.9     ++                                      ______________________________________                                         .sup.1) Diethanolamine was used as a pH adjusting agent.                 

As clearly shown by the results of Tables 2 and 3, the concentration ofcitric acid more than 2.5 (W/V) % gave stimulus on eyes regardless ofthe kind of citrate. As opposed to that, the aqueous compositions of thepresent invention gave no stimulus on eyes.

Test Example 3 (Test to examine the transition of timolol to albinorabbit aqueous humor)

In the method of Example 14, methylcellulose, sodium citrate and PEGwere replaced by 0.9 g of sodium chloride to prepare Composition 9.Moreover, in the method of Example 14, PEG was omitted to prepareComposition 10. The transition of timolol comprised in the compositionof Example 14 and Compositions 9, 10 to aqueous humor, was determined ineyes of male albino rabbits (body weight: 2.5-3.5 kg), of which 1 groupwas consisted of 6 eyes. 50 μl of the eye drops was instilled to thealbino rabbit eyes and the concentration of timolol in aqueous humor wasdetermined at 10 minutes, 30 minutes, 1 hour, 2 hours, 4 hours after theadministration. The results of this test are shown in Table 4.

                  TABLE 4                                                         ______________________________________                                        Concentration of timolol in aqueous humor(μg/ml)                           10                                                                            minutes     30 minutes                                                                              1 hour   2 hours                                                                              4 hours                                 ______________________________________                                        Ex. 14 1.2 ± 0.5                                                                           3.4 ± 0.9                                                                            3.0 ± 0.2                                                                         1.4 ± 0.3                                                                         0.2 ± 0.2                          Com. 9 0.5 ± 0.3                                                                           0.9 ± 0.4                                                                            0.9 ± 0.3                                                                         0.4 ± 0.1                                                                         0.1 ± 0.1                          Com. 10                                                                              0.7 ± 0.4                                                                           1.3 ± 0.3                                                                            0.9 ± 0.1                                                                         0.5 ± 0.0                                                                         0.1 ± 0.1                          ______________________________________                                    

As clearly shown by the results of Table 4, the aqueous composition ofthe present invention maintained high concentration for longer periodthan the eye drops which do not form gel in a local region.

Test Example 4 (Test to examine the transition of timolol to albinorabbit blood)

The transition of timolol comprised in the composition of Example 9 andComposition 9, was determined in albino rabbits (body weight: 2.5-3.5kg) of which 1 group consisted of 5 to 6 rabbits. 50 μl of the eye dropswas instilled to the albino rabbit eyes and the concentration of timololin blood was determined at 10 minutes, 30 minutes, 1 hour, 2 hours, 4hours and 6 hours after the administration. The results of this test areshown in FIG. 2.

As clearly shown by the results of FIG. 2, the aqueous composition ofthe present invention represses the transition of timolol to blood andmay decrease the systemic side effects in compare with the eye dropswhich do not form gel in a local region.

We claim:
 1. An aqueous drug composition having a property of reversiblethermosetting gelation, comprising an effective amount of one or moredrugs used in pharmaceutical therapy or diagnosis, wherein thecomposition comprises 0.2 to 2.1 (W/V) % of methylcellulose having acontent of methoxyl group within the range of 26 to 33%; 1.2 to 2.3(W/V) % of citric acid, 0.5 to 13 (W/V) % of polyethylene glycol and apharmaceutically acceptable pH adjusting agent in an amount sufficientto adjust the pH of the composition within a range of 3 to 10;andwherein said polyethylene glycol has a weight-average molecularweight of 300 to 50,000.
 2. The aqueous drug composition according toclaim 1, suitable for ophthalmic use, wherein the pharmaceuticallyeffective drug is selected from the group consisting ofchemotherapeutics, antibiotics preparation, antiallergic agents,anti-inflammatory agents, miotics and preparations, vitaminpreparations, vasoconstrictors, antihistamines, mydriatics andpreparations, antiglaucoma drugs, anticataract drugs, local anesthetics,ophthalmic diagnostic agents, immunosuppressive agents, antimetabolicagents, decongestants, autonomic nerve agents, anti diabetic retinopathyagent, amino acids and mixtures thereof.
 3. The composition according toclaim 2, wherein the drug is selected from the group of compoundsconsisting of amphotericin B, norfloxacin, miconazole nitrate,ofloxacin, idoxuridine, chloramphenicol, colistin sodiummethanesulfonate, carbenicillin sodium, gentamicin sulfate, ketotifenfumarate, sodium cromoglicate, 3-(1H-tetrazole-5-yl) oxanilic acid,betamethasone sodium phosphate, dexamethasone, fluorometholone,glycyrrhizinate dipotassium, lysozyme chloride, diclofenac sodium,pranoprofen, indomethacin, cortisone acetate, azulene, allantoin,ε-aminocaproic acid, pilocarpine hydrochloride, carbachol, flavinadenine dinucleotide, pyridoxal phosphate, cyanocobalamin, naphazolinenitrate, phenylephrine hydrochloride, chlorpheniramine maleate,diphenhydramine hydrochloride, tropicamide, timolol maleate, carteololhydrochloride, glutathione, pirenoxine, oxybuprocaine hydrochloride,lidocaine hydrochloride, fluorescein sodium, ciclosporin, azathioprine,fluorouracil, tegafur, epinephrine hydrochloride, neostigminemethylsulfate, [5-(3-thienyl)tetrazol-1-yl]acetic acid and chondroitinsulfate sodium.
 4. The composition according to claim 2, wherein thechemotherapeutics is idoxuridine or norfloxacin, the antibioticspreparation is gentamicin sulfate, the antiallergic agent is3-(1H-tetrazol-5-yl)oxanilic acid or sodium cromoglicate, theanti-inflammatory agent is betamethasone sodium phosphate orpranoprofen, the vitamin preparation is flavin adenine dinucleotide, thelocal anesthetics is lidocaine hydrochloride, the vasoconstrictors isnaphazoline nitrate, the miotics and preparation is pilocarpinehydrochloride, the antiglaucoma drug is timolol maleate, theanticataract drug is pirenoxine, the immunosuppressive agent isciclosporin, the antimetabolic agent is fluorouracil, the ophthalmicdiagnostic agent is fluorescein sodium, the mydriatics and preparationis tropicamide and the anti diabetic retinopathy agent is[5-(3-thienyl)tetrazol-1-yl ]acetic acid.
 5. The aqueous drugcomposition according to claim 1, suitable for local or dermatologicaluse, wherein the pharmaceutically effective drug is selected from thegroup consisting of anti-dermoinfectives, dermatics for purulence,analgesics and anti-inflammatory agents, anti-itchings, localanesthetics and antimicrobials for dermatologic use.
 6. The compositionaccording to claim 5, wherein the drug is selected from the compoundsconsisting of clotrimazole, salicylic acid, bifonazole, siccanin,bisdequalinium acetate, sulfamethoxazol sodium, erythromycin, gentamicinsulfate, indomethacin, ketoprofen, diphenhydramine, procainehydrochloride, lidocaine hydrochloride, iodine, povidone iodine,benzalkonium chloride, chlorhexidine gluconate, betamethasone valerateand fluocinolone acetonide.
 7. The composition according to claim 5,wherein the anti-dermoinfectives is clotrimazole, the dermatics forpurulence is gentamicin sulfate, the analgesics and anti-inflammatoryagent is indomethacin, the anti-itchings is diphenhydramine, the localanesthetics is lidocaine hydrochloride and the antimicrobials fordermatologic use is povidone iodine.
 8. The aqueous drug compositionaccording to claim 1 therefore, suitable for administration into bodycavities wherein the pharmaceutically effective drug is selected fromthe group consisting of antihistamines, agents affecting genital organs,agents for otic and nasal use, bronchodilators, antimetabolic agents,hypnotics and sedatives, antipyretics, analgesics and anti-inflammatoryagents, adrenal hormone preparations, local anesthetics, dermatics forpurulence and synthetic antibacterials.
 9. The composition according toclaim 8, wherein the drug is selected from the compounds consisting ofdiphenhydramine hydrochloride, chlorpheniramine maleate, clotrimazole,miconazole nitrate, tetryzoline hydrochloride, naphazoline nitrate,ketotifen fumarate, aminophylline, fluorouracil, diazepam, aspirin,indomethacin, sulindac, phenylbutazone, ibuprofen, dexamethasone,triamcinolone, hydrocortisone, lidocaine hydrochloride, sulfisoxazole,kanamycin, tobramycin, erythromycin, norfloxacin and nalidixic acid. 10.The composition according to claim 8, wherein the antihistamines isdiphenhydramine hydrochloride, the agent affecting genital organs ismiconazole nitrate, the agent for otic and nasal use is tetryzolinehydrochloride, the bronchodilators is aminophylline, the antimetabolicagent is fluorouracil, the hypnotics and sedatives is diazepam, theantipyretics, analgesics and anti-inflammatory agent is indomethacin,the adrenal hormone preparation is dexamethasone, the local anestheticsis lidocaine hydrochloride, the dermatics for purulence is erythromycinand the synthetic antibacterials is norfloxacin.
 11. The compositionaccording to claim 1, wherein 2.0% aqueous solution of themethylcellulose has a viscosity of 13 to 12,000 millipascal.sec at 20°C.
 12. The composition according to claim 1, wherein the compositionshows the gelling temperature of from about 20° C. to about 40° C. andthe composition is liquid at the temperature below it.
 13. Thecomposition according to claim 1, wherein the composition furthercomprises at least one of pharmaceutically acceptable buffers, salts,preservative or solubilizing agents.